PICALM: Role in the pathogenesis and treatment of Alzheimer vascular blood-brain barrier clearance dysfunction, neuronal dysfunction, and amyloid-beta, tau and neurodegenerative disorders

PICALM:在阿尔茨海默病血管血脑屏障清除功能障碍、神经元功能障碍以及 β 淀粉样蛋白、tau 蛋白和神经退行性疾病的发病机制和治疗中的作用

基本信息

  • 批准号:
    10420229
  • 负责人:
  • 金额:
    $ 241.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PICALM is one of the most significant susceptibility factors for late onset Alzheimer’s disease (LOAD). Its role in disease pathogenesis, however, remains elusive. We also do not have an effective PICALM-based therapy for AD. PICALM controls internalization of cell receptors, and intracellular trafficking of different proteins. PICALM is abundantly expressed in brain endothelium and neurons, but is reduced in LOAD and by some PICALM SNPs. To understand how PICALM regulates vascular and neuronal function and AD pathology, we developed new mouse models with PICALM-specific deletion from endothelium and neurons. The proposed studies are supported by our pilot data showing: i) that PICALM controls amyloid-β (Aβ) and tau clearance across the blood- brain barrier (BBB) and guides their trans-endothelial BBB transcytosis, and that PICALM endothelial deficiency leads to Aβ and tau brain accumulation; and ii) that PICALM loss from neurons leads to neuron loss, and renders them susceptible to both excitotoxic injury due to N-methyl-D-aspartate receptors (NMDAR) overexpression, and elevated Aβ and tau toxicity resulting from diminished PICALM binding to, and sequestration of glucose regulated protein 78 (GRP78) in the cytosol. This in turn shuttles free GRP78 to endoplasmic reticulum (ER) hampering unfolded protein response (UPR) which aggravates ER stress response to Aβ and tau. Since PICALM deficiency leads to loss-of-function, we propose to test therapies to increase PICALM with artesunate, a lead drug from our pilot FDA-approved library screen, and with gene therapy. We also generated a new Picalm465R line carrying a rare 465R PICALM missense mutation that does not alter PICALM expression, but increases its binding to GRP78 in neurons and LRP1 in endothelium. Based on our pilot data, we hypothesize that PICALM endothelial deficiency will lead to Aβ and tau brain accumulation due to their impaired clearance at the BBB caused by loss of PICALM binding to LRP1 and its deficient interactions with Rab5 and Rab11 during PICALM-guided Aβ and tau BBB transcytosis; whereas PICALM neuronal deficiency will render neurons susceptible to excitotoxic injury due to NMDAR overexpression, and will increase Aβ and tau neuronal toxicity by increasing GRP78 translocation from the cytosol to ER that will hamper UPR and augment ER stress response to Aβ and tau. Therapies to increase PICALM, and 465R mutant with enhanced binding to LRP1 and GRP78, will increase Aβ and tau BBB clearance and protect neurons. We will study the effects of endothelium-specific (AIM 1) and neuron-specific (AIM 2) PICALM deficiency on vascular and neuronal function and AD pathology; and the effects of artesunate and AAV-PHP.B-Picalm gene therapy (AIM 3), and the H465R PICALM mutation (AIM 4) on vascular and neuronal function and AD pathology. We will next identify molecular steps in Aβ and tau BBB transcytosis and neuronal toxicity regulated by PICALM using BBB models and neurons from human rs3851179 PICALM variants and Picalm465R mice (AIM 5). If successful, this proposal will generate unique new insights into PICALM biology with implications for better understanding of the role of PICALM in the pathogenesis and treatment of AD.
PICALM是晚发性阿尔茨海默病(LOAD)最重要的易感因素之一。的作用 然而,疾病的发病机理仍然是难以捉摸的。我们也没有有效的基于PICALM的治疗方法, ad. PICALM控制细胞受体的内化和不同蛋白质的细胞内运输。PICALM 在脑内皮和神经元中大量表达,但在LOAD中和通过一些PICALM SNP降低。 为了了解PICALM如何调节血管和神经元功能以及AD病理,我们开发了新的 内皮细胞和神经元中PICALM特异性缺失的小鼠模型。拟议的研究是 我们的初步数据支持:i)PICALM控制淀粉样蛋白-β(A β)和tau在血液中的清除, 脑屏障(BBB),并指导其跨内皮BBB转胞吞,而PICALM内皮缺陷 导致A β和tau脑积累;和ii)神经元的PICALM损失导致神经元损失,并使 由于N-甲基-D-天冬氨酸受体(NMDAR)过表达,它们对兴奋性毒性损伤敏感, 由于PICALM与葡萄糖调节蛋白的结合和隔离减少而导致A β和tau毒性升高 蛋白78(GRP78)。这反过来又将游离的GRP78穿梭到内质网(ER),从而阻碍 未折叠蛋白反应(UPR),其使ER对A β和tau的应激反应发生变化。由于PICALM缺陷 导致功能丧失,我们建议用青蒿琥酯测试治疗方法来增加PICALM,青蒿琥酯是我们的一种主要药物。 试验性FDA批准的文库筛选和基因治疗。我们还生成了一条新的Picalm465R线, 一种罕见的465R PICALM错义突变,不改变PICALM表达,但增加其与 神经元中的GRP78和内皮中的LRP 1。根据我们的初步数据,我们假设PICALM内皮细胞 缺乏会导致A β和tau在脑内蓄积,这是由于它们在BBB的清除率受损而造成的损失 PICALM与LRP 1的结合及其与Rab5和Rab11的相互作用缺陷, tau BBB转胞吞作用;而PICALM神经元缺陷将使神经元对兴奋性毒性损伤敏感 由于NMDAR过表达,并将通过增加GRP78易位而增加A β和tau神经元毒性 从细胞质到ER,这将阻碍UPR并增加ER对A β和tau的应激反应。疗法来 PICALM增加,以及与LRP 1和GRP78结合增强的465R突变体将增加A β和tau BBB 清除和保护神经元。我们将研究内皮特异性(AIM 1)和神经元特异性 (AIM 2)PICALM缺乏对血管和神经元功能以及AD病理学的影响;以及青蒿琥酯的影响 和AAV-PHP. B-Picalm基因治疗(AIM 3),以及H465 R PICALM突变(AIM 4)对血管和 神经元功能和AD病理学。我们接下来将鉴定A β和tau BBB转胞吞作用中的分子步骤, 使用BBB模型和来自人rs3851179 PICALM变体的神经元通过PICALM调节的神经元毒性 和Picalm465R小鼠(AIM 5)。如果成功,该提案将对PICALM生物学产生独特的新见解 这对更好地理解PICALM在AD发病机制和治疗中的作用具有重要意义。

项目成果

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Berislav V Zlokovic其他文献

RETRACTED ARTICLE: Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C
撤回文章:组织型纤溶酶原激活剂的神经血管毒性由活化蛋白 C 控制
  • DOI:
    10.1038/nm1122
  • 发表时间:
    2004-10-31
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Dong Liu;Tong Cheng;Huang Guo;José A Fernández;John H Griffin;Xiaomei Song;Berislav V Zlokovic
  • 通讯作者:
    Berislav V Zlokovic
RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system
撤回文章:周细胞变性导致小鼠中枢神经系统白质功能障碍
  • DOI:
    10.1038/nm.4482
  • 发表时间:
    2018-02-05
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Axel Montagne;Angeliki M Nikolakopoulou;Zhen Zhao;Abhay P Sagare;Gabriel Si;Divna Lazic;Samuel R Barnes;Madelaine Daianu;Anita Ramanathan;Ariel Go;Erica J Lawson;Yaoming Wang;William J Mack;Paul M Thompson;Julie A Schneider;Jobin Varkey;Ralf Langen;Eric Mullins;Russell E Jacobs;Berislav V Zlokovic
  • 通讯作者:
    Berislav V Zlokovic

Berislav V Zlokovic的其他文献

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{{ truncateString('Berislav V Zlokovic', 18)}}的其他基金

Activated protein C mechanisms of brain white matter protection and new therapies for brain white matter ischemic injury
激活蛋白C脑白质保护机制及脑白质缺血性损伤新疗法
  • 批准号:
    10208987
  • 财政年份:
    2020
  • 资助金额:
    $ 241.07万
  • 项目类别:
Biomarker Core
生物标志物核心
  • 批准号:
    10247459
  • 财政年份:
    2020
  • 资助金额:
    $ 241.07万
  • 项目类别:
Biomarker Core
生物标志物核心
  • 批准号:
    9922632
  • 财政年份:
    2020
  • 资助金额:
    $ 241.07万
  • 项目类别:
Activated protein C mechanisms of brain white matter protection and new therapies for brain white matter ischemic injury
激活蛋白C脑白质保护机制及脑白质缺血性损伤新疗法
  • 批准号:
    10029601
  • 财政年份:
    2020
  • 资助金额:
    $ 241.07万
  • 项目类别:
Biomarker Core
生物标志物核心
  • 批准号:
    10655669
  • 财政年份:
    2020
  • 资助金额:
    $ 241.07万
  • 项目类别:
Project 3 - Animal Models Examining Neurovasculature
项目 3 - 检查神经脉管系统的动物模型
  • 批准号:
    10331686
  • 财政年份:
    2016
  • 资助金额:
    $ 241.07万
  • 项目类别:
The role of pericytes in white matter disease
周细胞在白质疾病中的作用
  • 批准号:
    9762993
  • 财政年份:
    2016
  • 资助金额:
    $ 241.07万
  • 项目类别:
Project 3 - Animal Models Examining Neurovasculature
项目 3 - 检查神经脉管系统的动物模型
  • 批准号:
    10621719
  • 财政年份:
    2016
  • 资助金额:
    $ 241.07万
  • 项目类别:
Core B - Biomarkers
核心 B - 生物标志物
  • 批准号:
    10621700
  • 财政年份:
    2016
  • 资助金额:
    $ 241.07万
  • 项目类别:
Core B - Biomarkers
核心 B - 生物标志物
  • 批准号:
    10331682
  • 财政年份:
    2016
  • 资助金额:
    $ 241.07万
  • 项目类别:
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